The principal mediator of androgenic activity in some target organs, e.g., the prostate, is 5.alpha.-dihydrotestosterone ("DHT"), formed locally in the target organ by the action of 5.alpha.-reductase, which converts testosterone to DHT. Certain undesirable physiological manifestations, such as acne vulgaris, seborrhea, female hirsutism, androgenic alopecia (also called androgenetic alopecia) which includes female and male pattern baldness, and benign prostatic hyperplasia, are the result of hyperandrogenic stimulation caused by an excessive accumulation of testosterone ("T") or similar androgenic hormones in the metabolic system. Inhibitors of 5.alpha.-reductase will serve to prevent or lessen symptoms of hyperandrogenic stimulation in these organs. See especially U.S. Pat. No. 4,377,584, issued Mar. 22, 1983, and U.S. Pat. No. 4,760,071, issued Jul. 26, 1988, both assigned to Merck & Co., Inc. It is now known that a second 5.alpha.-reductase isozyme exists, which interacts with skin tissues, especially in scalp tissues. See, e.g., G. Harris, et al., Proc. Natl. Acad. Sci. USA, Vol. 89, pp. 10787-10791 (November 1992). The isozyme that principally interacts in skin tissues is conventionally designated as 5.alpha.-reductase 1 (or 5.alpha.-reductase type 1), while the isozyme that principally interacts within the prostatic tissues is designated as 5.alpha.-reductase 2 (or 5.alpha.-reductase type 2).
U.S. Pat. No. 5,237,064 describes a process for producing 7.beta.-substituted 5.alpha.-androstan-3-ones. U.S. Pat. No. 5,470,976 describes the stereoselective hydrogenation of the delta-5 double bond of a 17-substituted azasteroid. U.S. Pat. No. 5,120,847 and U.S. 5,021,575 relate to the insertion of a double bond at the 1,2 position of a 4-azasteroid.
The instant invention provides an improved process for the synthesis of 16-substituted 7-.beta.-methyl-4-aza-5.alpha.-androst-1-en-3-ones. 16.beta.-substituted 7-.beta.-methyl-4-aza-5.alpha.-androst-1-en-3-ones are described in PCT publication WO 95/11254. Also provided by the present invention are intermediates useful in the present process.